Project Summary/Abstract The purpose of this K23 application is to support my short-term career objectives of acquiring multimodal neuroimaging, neurocomputational, biostatistical, and theoretical social cognitive knowledge in the study of anxiety and emotion regulation in youth at high-risk for bipolar disorder (BD). Longitudinal evidence suggests that youth at high-risk for BD that develop any mood disorder experience an anxiety disorder as an early antecedent. Anxiety is therefore an important symptom in the developmental trajectory of BD. One of the largest sources of anxiety in youth is the quality of social relationships, which greatly influence youth's perceived quality of life. However, little is known about the neural underpinnings of social cognition in youth at high-risk for BD or how everyday social interactions affect anxiety and emotion regulation, which is a hallmark characteristic of BD. In a previous pilot study (P.I. Roybal, American Academy of Child and Adolescent Psychiatry/Lilly Pilot Research Award), I showed differences in brain activation and functional connectivity between youth with BD relative to healthy controls (HC) when both groups experienced a functional magnetic resonance imaging (fMRI) social rejection task. I applied this fMRI social rejection task to youth at high-risk for BD (P.I. Roybal, Hogg Foundation for Mental Health). The research proposed here will add to the sample size of this high-risk group (HR) as it proposes to use the same fMRI social rejection task and add on an fMRI task evaluating perceived internal threat subsequent to social rejection. Behavioral assessments and fMRI will be used to assess functional neuroanatomical correlates in the HR group. Our hypotheses predict that the HR group will have functional neural deficits relative to HC during a social rejection task that involve regions salient to social rejection, specifically subgenual anterior cingulate cortex and anterior insula, but also will involve limbic areas not typically seen in social rejection, specifically the amygdala and hippocampus. We hypothesize that within the HR group, hyperactivation and abnormal connectivity observed during the social rejection task will correlate with subsequent anxiety felt after experiencing social rejection. We will also examine the effects of social rejection on internal threat cues that affect mood. We hypothesize the HR group will exhibit greater amygdala activation and weaker functional connectivity between amygdala and prefrontal cortex, a structure theorized to regulate the amygdala, relative to HC. Within the HR group, abnormal activation and connectivity will be correlated with the ability to emotionally self-regulate. Both treating youth with and at high-risk for BD and having basic neuroimaging experience have laid a solid foundation for me to achieve my training goals and complete this study. The proposed integrated research, mentorship, and didactic training programs, combined with the outstanding research environment at the University of Texas Health Science Center at San Antonio, will foster my long-term career objective of being a leading expert in multimodal social cognitive neural models as they relate to anxiety and emotion regulation in children at high-risk for BD.